Elucidating Serotonergic Mechanisms Regulating Cardiovascular Recovery After Grafting Embryonic Raphe Neurons into the Injured Rat Spinal Cord

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Spinal cord injury (SCI) at the 6th thoracic level (T6) or above often results in the loss of supraspinal regulation over cardiovascular function. This dysfunction manifests as abnormal resting hemodynamics and the development of orthostatic hypotension and autonomic dysreflexia (AD). Collectively, these irregularities mark cardiovascular dysfunction as one of the leading causes of morbidity and mortality among the population. Although there are current pharmacological and preventative measures in place to mitigate these issues, they lack long-term efficacy and do not address the underlying loss of supraspinal connectivity. Recently, we discovered grafting raphe nuclei-derived neural progenitors/stem cells (RN-NPCs) after SCI partially restores hemodynamic regulation. More specifically, we found that the graft restores connectivity between raphe nuclei cell populations and sympathetic preganglionic neurons in the spinal cord. Moreover, silencing serotonergic receptor 5HT2A resulted in the loss of functional recovery. Therefore, we hypothesize that functional recovery after grafting is centrally mediated through supraspinal and intraspinal serotonergic mechanisms. In Aim 1, we will graft RN-NPCs into rats sustaining a T4 crush injury and measure cardiovascular output including resting hemodynamics, and AD frequency and severity. Subsequently, we will reinjury the rats above the transplant site and reevaluate all hemodynamic parameters. This will determine if functional restoration is contingent on supraspinal connectivity with the graft. In Aim 2, we will employ chemogenetic techniques to silence serotonergic neurons of the host caudal raphe nuclei after RN-NPC grafting to identify if supraspinal serotonergic regulation of cardiovascular function has been reestablished. In Aim 3, we will use the same chemogenetic tools to silence graft-derived serotonergic neurons, elucidating if these neurons facilitate hemodynamic restoration. We will also administer serotonergic and noradrenergic receptor antagonists to examine which spinal receptors are involved in reestablishing cardiovascular regulation. Collectively, these results will provide guidance for potential clinical translation to mitigate hemodynamic dysfunction after SCI.